The primary genetic risk factor for Alzheimer's disease (AD) is inheritance of the APOE4 gene for apolipoprotein E (apoE), increasing the risk approximately 15-fold with APOE4+/+, whereas inheritance of APOE2 reduces risk. APOE4 carriers account for more than half of AD patients, and exhibit a differential response to certain therapeutic interventions, which can contribute to the failure of clinical trials. The strikingly hgh-risk for AD caused by APOE4 and clear evidence for synergistic actions with amyloid-beta peptide (Abeta), point to the urgent need to develop therapeutic approaches that incorporate the APOE genotype and A beta pathology. Recently, the RXR agonist, bexarotene (BEX), was reported to increase mouse-apoE levels, decrease soluble Abeta within hours, insoluble Abeta after three days, and restore cognition in transgenic mice expressing familial AD mutations. However, extrapolation of the mouse data to AD patients is problematic since the studies did not incorporate human-apoE isoforms. Genetic data demonstrates that lowering human-apoE levels actually decreases Abeta pathology in; furthermore, APOE4 represents a toxic gain of function as assessed by markers of synapse viability in vitro and in vivo. Our hypothesis is that RXR agonist-induced attenuation of Abeta pathology is differentially modulated by APOE genotype. Results from this proposed study will be both timely and critical, as BEX is currently entering phase 1 clinical trials; and will inform the design of future clinical trials on RXR agonists, including dosage and the inclusion of APOE4 subjects. BEX will be studied in parallel with LG268 as it has greater RXR selectivity (over RAR), and GRT63, a novel homologue. While all three RXR agonists have high oral brain bioavailability, LG268 and GRT63 have improved physicochemical characteristics. Aim 1 will establish predictive PK/PD and DMPK properties for BEX, LG268 and GRT63 to direct the in vivo strategy to test treatment paradigms in EFAD-Tg mice (Aim 2), an innovative model which expresses human APOE and overexpress Abeta 42. Aim 1 will determine the PK/PD for RXR agonists in vitro and in vivo, by establishing target engagement (LXRE-luciferase construct), RXR biomarker validation (ABCA1/ABCG1, apoE, induction of cytokines IL-1 beta and TNF-alpha) in multiple cell lines, and identifying an effectiv oral dose for each agonist. Metabolic stability in liver microsomes and PK and body weight in vivo will be measured. Aim 2 will determine the therapeutic efficacy of RXR agonists in EFAD mice using efficacious doses identified in Aim 1, comparing E4FAD and E3FAD mice. The RXR-mediated elevation of APOE3 is proposed to be beneficial, characterized by reduced A beta pathology and inflammatory cytokines, and reversal of synaptic protein loss and behavioral deficits. However, RXR induction of ABCA1/ABCG1 may provide a greater net beneficial effect in APOE4 carriers, as apoE4 may be less lipidated, resulting in a partial loss of function compared with apoE3. These studies will determine the efficacy of RXR agonists in the presence of APOE3 and APOE4 in a highly innovative animal model of AD.